Warfarin Sensitivity Testing
A health practitioner might order this test prior to prescribing warfarin for you if there is a history of warfarin resistance in your family, or more commonly, a health practitioner may sometimes order it when you are being treated with warfarin and have had bleeding or clotting episodes or difficulties in achieving a therapeutic dose of warfarin as determined by blood monitoring.
A blood sample taken from a vein in your arm
Warfarin (Coumadin®) is a "blood-thinner" (anticoagulant), a drug that is commonly prescribed to help prevent inappropriate blood clots forming (thrombosis and thromboembolism) in individuals who are at risk, such as those with prosthetic heart valves or with atrial fibrillation, or to help keep an existing blood clotting condition from getting worse. Warfarin sensitivity testing helps determine if a person may be more sensitive (i.e., require lower doses) or, less commonly, resistant (i.e., require higher doses) to treatment with warfarin because of his or her genetic makeup. Testing usually involves looking for common genetic variations in two genes, CYP2C9 and VKORC1. A health practitioner may sometimes order this test to help select appropriate doses of warfarin and/or to achieve appropriate dose levels more quickly.
Warfarin can be a challenging drug to administer and monitor because its levels can be affected by many different factors and it has a narrow window in which it is effective. If a person is given too little drug, he or she may be at risk of forming a blood clot; if given too much drug, he or she may be at risk of moderate to severe bleeding episodes. The range between too much drug and too little drug is small and it varies significantly from person to person.
Standard warfarin doses based upon age, weight, and sex are prescribed to those starting treatment. The effect of the drug is closely monitored during the first few days and weeks of treatment using frequent PT/INR (prothrombin time/international normalized ratio) tests to determine the medication's anticoagulant ("blood-thinning") effect, which allows trained medical staff to alter the dosing to try and achieve the correct therapeutic dose of the drug in the patient’s blood. Health practitioners then use periodic PT/INR tests to ensure that a stable dose with sufficient anticoagulation has been achieved. Although this dosing strategy is still commonly used, it can take as long as several weeks to stabilise individuals on the drug.
Genetic testing for warfarin sensitivity may help health practitioners to tailor prescription and shorten the time it takes for some people to reach a stable dose; that is, to achieve adequate "blood-thinning" without bleeding episodes. Most often, it is determined that people are more sensitive to warfarin and may need smaller doses; however, there are some people who are less sensitive and may need larger doses. The reason for the relative sensitivity can be, at least in part, due to the individual's genetic makeup and may involve two genes:
- The VKORC1 gene codes for the production of a protein (VKOR) that is involved in the production of functional forms of certain clotting factors (II, VII, IX, X) that allows them to participate in the clotting process and enable formation of a blood clot. Warfarin prevents the action of VKOR and is known as a vitamin K antagonist. Therefore, a variation in VKORC1 may cause someone to be more or less sensitive (or resistant) to warfarin.
- The CYP2C9 gene codes for the production of a protein (CYP2C9) involved in the breakdown (metabolism) of warfarin. People with CYP2C9 variations may not be able to get the drug out of their system as efficiently as others. These people who clear the drug more slowly may require lower (sometimes significantly lower) doses of warfarin.
Each person receives one copy of each of their genes from their mother and one copy of each of their genes from their father. Thus, each of the CYP2C9 and VKORC1 genes is present in the body as two inherited gene copies (genes). Any person could have both copies of a gene without any variants (wild-type); one copy without variants and one copy with a variant (heterozygous); both copies with the same variant (homozygous); and both copies with different variants ("compound heterozygous"). The combination of CYP2C9 and VKORC1 gene copies that a person has can determine the overall effect of warfarin and how rapidly it is metabolised and cleared from the body.
Warfarin sensitivity (or warfarin genotype) testing determines whether CYP2C9 and VKORC1 gene variants are present. Careful interpretation of the results can help the health practitioner decide the appropriate doses of warfarin for the person tested.
How is the sample collected for testing?
A blood sample is obtained by inserting a needle into a vein in the arm.
Is any test preparation needed to ensure the quality of the sample?
No test preparation is needed.
How is it used?
Warfarin sensitivity testing (genotyping) may be used to help determine someone's likely sensitivity or, less commonly, resistance to warfarin and to help select appropriate doses. Warfarin (Coumadin®) is an anticoagulant, a drug that is prescribed to help prevent inappropriate blood clotting (thrombosis and thromboembolism) in people who are at risk, or to help keep an existing blood clotting condition from getting worse.
Warfarin genotyping identifies variations in certain genes.
- The VKORC1 gene codes for the protein that warfarin targets. A variation in this gene may result in a protein change that may be more sensitive or less sensitive (or resistant) to the anticoagulant effect of warfarin. Depending on the variant present, the person tested may need a lower or higher initial dose of warfarin.
- The CYP2C9 gene codes for a protein involved in the breakdown (metabolism) of warfarin. People with variations in this gene may metabolize warfarin more slowly, resulting in slower clearance of the drug and accumulation in the body over time. They may require a lower dose of the drug.
This testing may sometimes be used to help determine an appropriate dose for a person who has previously taken warfarin and either experienced inappropriate clotting or bleeding episodes while on warfarin or had to go through many dose adjustments to reach a stable anticoagulant ("blood-thinning") effect.
CYP2C9 and VKORC1 genetic testing is not widely used. Although studies have shown that these genes contribute to a person's sensitivity to warfarin and can account for a significant percentage of the person-to-person variation in warfarin doses, there is not a consensus on the need for the testing yet as a wide range of factors can contribute to the ability to achieve a stable therapeutic dose of warfarin (including lifestyle, diet and other genetic factors).
When is it requested?
Warfarin sensitivity testing may rarely be ordered prior to a person taking warfarin for the first time but would usually only be considered if a person has had difficulties with achieving a stable anticoagulant ("blood-thinning") effect or has experienced either excessive blood clotting or bleeding whilst on the drug.
Not everyone who is prescribed warfarin will have this test done. At present, there is no consensus on the usefulness of this test and it is not yet widely accepted or available.
What does the test result mean?
Warfarin sensitivity testing will identify the CYP2C9 and VKORC1 genetic variants (i.e., genotype) present for the person tested. The results must be interpreted carefully to help determine if the person is likely to need a relatively lower or higher dose of warfarin. These results are interpreted by a specialist.
Those who have one or more variant CYP2C9 or VKORC1 gene copies are more likely to need a lower or higher dose of warfarin. The amount needed will depend on the number and type of genetic variants present but will also greatly depend upon a person's other factors, including health, age, sex, diet, and other medications.
This test detects only the most common genetic variants in CYP2C9 and VKORC1. A person may have a rare variant, resulting in a negative test result, but may still be more sensitive or resistant to warfarin.
Is there anything else I should know?
Warfarin sensitivity testing is not widely available in the UK and is reserved for patients in whom there are issues with stabilisation. There have been many studies conducted in this area but there is still not a general consensus on the use of these tests prior to prescribing the drug.
Warfarin sensitivity/resistance is a well-described phenomenon and close contact with medical staff during the first few weeks of warfarin prescription with monitoring of the therapeutic effect of the drug quickly identifies those individuals in whom extended testing to check for genetic variants causing sensitivity/resistance should be considered. Alternative anticoagulant drugs are available for some conditions and may be considered in patients who prove resistance to stabilisation on warfarin.
Whatever the initial dosage of warfarin, each person taking warfarin will still need to be monitored with the PT/INR test and all subsequent dose adjustments will be made by taking these test results into account.
Many drugs interact with warfarin and can slow the metabolism of warfarin. Make sure all of your healthcare providers are aware of all the medications you are taking.
Warfarin is prescribed to those at risk for inappropriate clotting, including those who have had a previous blood clot; those with excessive clotting disorders, atrial fibrillation, artificial heart valves; and those who have undergone orthopaedic surgeries.
If I have genetic testing done, will I still need to be monitored with PT/INR tests?
Yes. Regardless of the results of the genetic testing, your response to warfarin therapy will still need to be monitored with regular PT/INR tests. This is because your individual degree of anticoagulation ("blood-thinning") can be affected by other factors such as diet, age, weight, other medications and state of health, which can change over time.
Can warfarin sensitivity testing be done in my doctor's office?
No, it requires specialised equipment to perform and expertise to interpret. It is not offered by every laboratory and may need to be sent to a laboratory outside of your hospital (i.e. reference laboratory).
Will I need to have this test done more than once?
Should I tell other doctors about my warfarin sensitivity?
Should my other family members be tested for warfarin sensitivity?
This is something to discuss with your healthcare provider and family. It is not generally indicated unless a family member is also going to be taking warfarin, but having a family member who has warfarin sensitivity is important information to keep in mind and to share with your health practitioner.